The incidence of arthritis and the antibody response to mouse and to rat type II collagen after immunization with native rat type II collagen was studied in different mouse strains, including wild mouse-derived strains belonging to the H-2p/H-2q family. High serum levels of antibodies to mouse and rat type II collagen were seen only in H-2q mice, whereas mice belonging to the p, w3, w5, and w17 haplotypes displayed low type II collagen-specific antibody responses. Mice from three different H-2q-carrying strains (DBA/1, NFR/N, and B10.G) with different non-major histocompatibility complex genes were all susceptible to collagen arthritis, but they displayed a varying incidence of arthritis and varying clinical features. No arthritis was seen in non-H-2q mice, except in the B10.CAS2 strain where a few mice developed arthritis despite very low serum levels of type II collagen-specific antibodies. We conclude that small differences in the A beta chain of class II transplantation antigens are of importance for the development of arthritis and for the stimulation of a high response after immunization with type II collagen.